The background of this research plan is the particular sensitivity of central neurons to decreased supply of oxygen (hypoxia/ischemia) or glucose (hypoglycemia). These pathological conditions constitute a major cause of acute neurological dysfunction associated with stroke, cardiac arrest, shock, brain concussion, insulin coma and some liver diseases. Thus, there is a major ethical, clinical and economical interest from the society to find measures to protect, prevent, or minimize brain damage associated with these insults. In this broader perspective the application represents an effort to elucidate the basic molecular mechanism underlying neuronal necrosis and their amelioration. The basis of our working hypothesis is the proposal made by Vogt and Vogt 1937, stating that the specific physico-chemical properties of certain neuronal populations make them particularly prone to these insults. We propose that the neurons are specially sensitive to these insults as a result of both specific transmitter input and transmitter receptor characteristics. We hypothesize that in the postischemic and posthypoglycemic period an imbalance prevails between the release of excitatory and inhibitory neurotransmitters and neuromodulators. This imbalance leads to a deranged metabolic and cellular homeostasis ultimately leading to cell death. In this application we propose to put the transmitter-receptor hypothesis to a thorough and detailed scrutiny. Our objective is to investigate the regional changes in the extracellular levels of amino acids, biogenic amines and noradrenaline turnover using microdialysis tecniques. We also aim to investigate receptor characteristics of the glutamate, adenosine and glycine receptors in vulnerable and resistant areas of the brain with autoradiographic techniques, and to study the effects of locally administered receptor agonists and antagonists and trophic factors on the development of ischemic and hypoglycemic damage in the hippocampus and the striatum.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS025302-03
Application #
3410574
Study Section
Neurology A Study Section (NEUA)
Project Start
1988-07-01
Project End
1991-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Lund University
Department
Type
DUNS #
350582417
City
Lund
State
Country
Sweden
Zip Code
SE-22-100
Wieloch, T; Bergstedt, K; Hu, B R (1993) Protein phosphorylation and the regulation of mRNA translation following cerebral ischemia. Prog Brain Res 96:179-91
Anderson, K J; Nellgard, B; Wieloch, T (1993) Ischemia-induced upregulation of excitatory amino acid transport sites. Brain Res 622:93-8
Nellgard, B; Wieloch, T (1992) NMDA-receptor blockers but not NBQX, an AMPA-receptor antagonist, inhibit spreading depression in the rat brain. Acta Physiol Scand 146:497-503
Nellgard, B; Gustafson, I; Wieloch, T (1991) Lack of protection by the N-methyl-D-aspartate receptor blocker dizocilpine (MK-801) after transient severe cerebral ischemia in the rat. Anesthesiology 75:279-287
Gustafson, I; Westerberg, E J; Wieloch, T (1991) Extracellular brain cortical levels of noradrenaline in ischemia: effects of desipramine and postischemic administration of idazoxan. Exp Brain Res 86:555-61
Cardell, M; Siesjo, B K; Wieloch, T (1991) Changes in pyruvate dehydrogenase complex activity during and following severe insulin-induced hypoglycemia. J Cereb Blood Flow Metab 11:122-8
Cardell, M; Boris-Moller, F; Wieloch, T (1991) Hypothermia prevents the ischemia-induced translocation and inhibition of protein kinase C in the rat striatum. J Neurochem 57:1814-7
Westerberg, E; Magnusson, K; Wieloch, T et al. (1990) Extracellular levels of quinolinic acid are moderately increased in rat neostriatum following severe insulin-induced hypoglycaemia. Acta Physiol Scand 138:417-22
Lauritzen, M; Hansen, A J; Kronborg, D et al. (1990) Cortical spreading depression is associated with arachidonic acid accumulation and preservation of energy charge. J Cereb Blood Flow Metab 10:115-22
Lundgren, J; Cardell, M; Wieloch, T et al. (1990) Preischemic hyperglycemia and postischemic alteration of rat brain pyruvate dehydrogenase activity. J Cereb Blood Flow Metab 10:536-41

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